PROJECT SUMMARY Pancreatic adenocarcinoma patients have a 5-year overall survival rate of less than 10%, unless these patients can undergo curative surgery. Patients who will undergo surgery first receive chemotherapy treatment to improve the likelihood of success of the surgery. However, the vast majority of patients are not surgical candidates due to disease dissemination, and are therefore treated with only a combination of multiple chemotherapies. For these patients as well as those who are candidates for surgery, improved chemotherapy efficacy would likely significantly improve survival rates. One way to improve chemotherapy efficacy is to increase delivery of chemotherapy specifically to the tumor by improving tumor vascular function. We have demonstrated in mouse models of pancreatic cancer that moderate aerobic exercise causes tumor vasculature to remodel and become more functional, leading to better chemotherapy delivery to the tumor and ultimately better anti-tumor efficacy. We also demonstrated that tumor vascular normalization in response to exercise is dependent on increased Thrombospondin-1 (TSP-1) in the serum. Importantly, our pilot study in human patients with pancreatic cancer patients demonstrated that a home-based aerobic and resistance exercise program is safe and feasible during the time after diagnosis, during chemotherapy, chemoradiation, and rest, prior to surgery. Here, we propose to evaluate tumor vascular remodeling and serum levels of TSP-1 to determine whether these are biomarkers of response to exercise, which we hypothesize will correlate with improved chemotherapy efficacy and thus better patient outcome. Patient outcome will include physical fitness and strength, as well as the percent of surgical candidates who are able to undergo surgery. We will evaluate blood and surgical tumor specimens, as well as patient outcomes, from patients in a randomized clinical trial comparing standard of care (recommendation to exercise) to a home-based, structured exercise program consisting of 150 minutes per week of walking and resistance exercise during the time that patients are actively receiving chemotherapy, chemoraidation, or are recovering prior to surgery.